脐血间充质干细胞来源微泡：让衰老MSCs"变年轻"的新策略

Mesenchymal stem cells(MSCs) rejuvenate our tissues but are not resistant to ageing themselves. New strategies and safe techniques are urged to rejuvenate aged MSCs. Compared with aged MSCs, umbilical cord blood(UCB)-derived MSCs are more capable of cellular proliferation, differentiation and tissue repair and regeneration. Since microvesicles(MVs) is able to orchestrate the dynamic stem cell microenvironment, with support of the findings in our previous tests, we hypothesize that MVs from UCB-derived MSCs might have potential abilities to rejuvenate aged MSCs with their selectively-enriched and horizontal transferred age-related miRNAs. This coming project will investigate the rejuvenation effect of the MVs from UCB-derived MSCs on aged MSCs. Meanwhile, we will make comparative study about the differential expression of the secreted age-related miRNAs in the MVs from UCB-derived and aged MSCs-MV, which will help to investigate and confirm the key molecular mechanism of rejuvenating aged MSCs and demonstrate the important role of the age-related miRNAs transferred horizontally from the MVs of UCB-MSCs to the aged MSCs to activate age-associated signals. Our study will help to provide a new strategy and technique to rejuvenate aged MSCs, which will present new approaches to optimize cell and tissue engineering and new ideas to improve the elderly declining physiological function and to treat the age-associated diseases.

间充质干细胞（MSCs）是人体自我修复和组织再生的重要干细胞来源，却难以抵抗自身衰老，寻找新型安全改造策略和手段十分重要。与老年衰老MSCs比，脐血MSCs具有旺盛的增殖分化及组织修复再生功能，基于微泡（MV）营造干细胞微环境、调控干细胞命运的关键作用，结合前期预实验结果，我们推测脐血MSCs-MV能够富集并向衰老MSCs横向传递调控衰老相关的miRNAs，进而改造和逆转其衰老。本项目以MV为切入点，研究脐血MSCs-MV对衰老MSCs的"年轻化"改造效应，比较脐血和衰老MSCs-MV中衰老相关miRNAs的表达差异，最后证实此类miRNAs横向传递进入衰老MSCs后对衰老相关调控信号是其关键分子机制。本课题研究衰老MSCs年轻化的新策略及分子机制，为优化MSCs这一临床重要的组织工程细胞提供新方法，也为提高老年衰退的生理功能以及治疗衰老相关性疾病提供新的策略和思路。

组织干细胞是分化形成组织器官中各类功能细胞的种子细胞。因此，组织干细胞的衰老是机体衰老的关键。间充质干细胞（MSCs）作为成体干细胞的一员，能够分化成骨髓微环境的主要细胞成分（成骨、脂肪、内皮细胞等），并且具有强大的造血支持和免疫调节作用。然而随机体年龄增加MSCs逐渐衰老，并伴随着其数量和功能的大幅度衰退。这一现象，严重影响骨髓微环境的自我修复、调节功能以及依赖于MSCs细胞治疗的效果，同时也是导致机体衰老及衰老相关退行性疾病的重要进展因素。本项目首先研究不同衰老状态脐带MSCs分泌MVs（MSCs-MV）的表型特征并寻找其miRNAs表达规律；进而确证早代脐带MSC-MVs携带更多的“年轻”信息；最后利用早代脐带MSCs-MV处理衰老的骨髓MSCs，发现其能逆转MSCs衰老相关表型。我们还对年轻大鼠和老年大鼠MSCs所分泌的MVs的miRNAs内含物进行比较，发现其表达谱明显不同；利用年轻大鼠MSCs来源的MVs与聚已内酯构成的新型复合材料具有更强的促进骨组织材料骨再生的能力。本项目提出了一种逆转MSCs衰老的新方法，为优化MSCs这一重要的组织工程细胞提供了一种新方案，也为治疗MSCs衰老相关疾病提供了一种新思路。